What you should know about your treatment with TORISEL (temsirolimus) injection

Transcription

1 Wyeth Support If you do not have prescription drug insurance or need help paying for TRISEL, Wyeth may be able to help. Please contact the TRISEL Reimbursement Support Program: TRISEL Reimbursement Support Program Phone: WYETH-NC ( ) Fax: Monday through Friday 9:00 a.m. to 6:00 p.m., Eastern Time Additional Support The organizations listed here can help you learn more about kidney cancer: American Cancer Society ACS-2345 ( ) Kidney Cancer Association Cancer.Net Please see Important Safety Information starting on page 2. For additional information about TRISEL, please see the Prescribing Information in the pocket. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call FDA , Wyeth Pharmaceuticals Inc., Philadelphia, PA November What you should know about your treatment with TRISEL (temsirolimus) injection Please review this information before you begin your treatment. Your doctor or nurse can answer any questions you may have. Please see Important Safety Information starting on page 2. Please see accompanying Prescribing Information.

2 What is TRISEL? TRISEL is a type of treatment for advanced renal cell carcinoma (RCC) TRISEL blocks a specific part of cells, including normal cells and cancerous kidney cells, and helps stop them from growing and dividing TRISEL may help stop the creation of new blood vessels that feed the advanced RCC cells TRISEL has been proven to extend survival longer than IFN- (another therapy) in patients with advanced RCC Renal cell carcinoma, also called RCC, is a type of kidney cancer. In advanced RCC, the cancer cells have spread to other parts of the kidney or body. Will I receive any medicine before I receive TRISEL? Before you begin treatment with TRISEL, your doctor may give you an antihistamine It is possible to have a serious allergic reaction even after you receive an antihistamine Tell your doctor or nurse if you are allergic to antihistamines Tell your doctor or nurse if you have any swelling around your face or difficulty breathing during or after treatment An antihistamine is a medicine that can help lower the chances of an allergic reaction. Benadryl is an example of a common antihistamine. An allergic reaction occurs when the body has a reaction to an allergen, such as food or medicine. Some signs of an allergic reaction include a rash, trouble breathing, feeling flushed, and chest pain. Benadryl is a registered trademark of Pfizer, its affiliates, related companies or its licensors or joint venture partners. Please see additional Important Safety Information on pages 7-9. Please see accompanying Prescribing Information. 1 2

3 How will TRISEL be given? TRISEL is given as an intravenous (IV) infusion You will receive TRISEL nce a week as an IV infusion lasting 30 to 60 minutes In a hospital, clinic, or doctor s office Your doctor may decide to stop treatment if Your disease gets worse You have side effects that are too serious An intravenous (IV) infusion is a common way of giving certain medicines. The medicine is contained in a bag or bottle hanging upside down. A thin tube connects the bag or bottle to a needle, which goes into a vein so that the medicine can enter the bloodstream directly. What precautions should I take during treatment with TRISEL? Before you begin treatment with TRISEL, tell your doctor or nurse about ALL MEDICINES you are taking, including Prescription medications, including but not limited to Antibiotics Anticonvulsants Antidepressants Antifungals Antivirals Blood pressure medications Blood thinners Dexamethasone Vaccines Nonprescription (over the counter) medications Vitamins Herbal supplements, including but not limited to St. John s Wort Avoid eating grapefruit or drinking grapefruit juice during the course of your treatment with TRISEL, including the time between treatments 3 Please see additional Important Safety Information on pages 7-9. Please see accompanying Prescribing Information. 4

4 What side effects can I expect from treatment? TRISEL can cause serious side effects The most common side effects are Rash Weakness/fatigue Mouth sores Nausea Swelling/fluid retention Loss of appetite TRISEL has caused hair loss in 2% of patients Patients are likely to experience increased blood sugar levels This may require treatment with or an increase in the dose of a medicine that lowers blood sugar levels Tell your doctor or nurse if you are thirstier than usual or urinate more often than usual Triglycerides are a type of fat found in the bloodstream. Patients are likely to experience an increase in cholesterol and/or triglycerides This may require treatment with or an increase in the dose of a medicine that lowers cholesterol and/or triglycerides Your blood may be tested before you begin treatment and at other times over the course of therapy Your doctor or nurse may have you fast (not eat or drink) before blood tests Examples of rash Courtesy of the Cleveland Clinic Taussig Cancer Center. Please see additional Important Safety Information on pages 7-9. Please see accompanying Prescribing Information. 5 6

5 7 What other Important Safety Information should I know about? Treatment with TRISEL may affect your immune system You may be at greater risk of getting an infection while receiving TRISEL Patients may get chronic inflammation of the lungs during treatment with TRISEL Rare fatal cases have been reported Tell your doctor or nurse right away if you have any trouble breathing, get a cough, or develop a fever TRISEL may cause bowel perforation Rare fatal cases have been reported Tell your doctor or nurse right away if you have any new or worsening stomach pain or blood in your stool The immune system is the part of the body that fights infections. When the immune system is weak, the body is more likely to be infected by bacteria and viruses that can cause infections. Chronic inflammation of the lungs is a condition in which the lungs become inflamed and swollen. Bowel perforation is a tear in the wall of the intestines. Treatment with TRISEL may be associated with a risk of kidney failure, sometimes fatal During treatment with TRISEL, wounds may not heal properly Tell your doctor or nurse if you are recovering or still have an unhealed wound from surgery Tell your doctor or nurse if you plan to have surgery during treatment with TRISEL TRISEL may increase the risk of bleeding in the brain, which has, in rare cases, been fatal. You are at increased risk if You have a central nervous system tumor, such as a brain tumor You are taking medicine to keep your blood from clotting The central nervous system includes the brain and spinal cord. Clotting is the ability of the blood to thicken to help stop bleeding. However, if a blood clot inside the body is too big, it could stop blood flow. Some people with blood clots or a high potential to develop blood clots must take medicine to stop their blood from clotting. Please see accompanying Prescribing Information. 8

6 What other Important Safety Information should I know about? (cont.) Helpful Tips Some vaccines may be less effective when given during the course of treatment with TRISEL You should avoid the use of live vaccines and close contact with people who have recently received live vaccines Ask your doctor or nurse if you are eligible to receive a flu shot Both men and women should use a reliable form of birth control during treatment and for 3 months after the last dose of TRISEL TRISEL can harm an unborn baby Tell your doctor or nurse before beginning treatment if you are pregnant or thinking of becoming pregnant Examples of live vaccines are Intranasal influenza Measles Mumps Rubella ral polio BCG Yellow fever Varicella TY21a typhoid vaccines Tell all your doctors you are taking TRISEL Arrange for a friend or family member to drive you to and from your weekly appointments Treatment with TRISEL may make you feel weak or sick Maintain good oral hygiene Basic oral care may help reduce the severity of potential mouth sores Talk to your doctor or nurse about diet and exercise An exercise program and balanced diet may help manage potential fatigue Tell your doctor or nurse about any changes in the way you look or feel during treatment 9 Please see accompanying Prescribing Information. 10

7 Notes Notes 11 Please see Important Safety Information starting on page 2. Please see accompanying Prescribing Information. 12

8 Notes Talk to your doctor or nurse if you have any questions about treatment with TRISEL. To learn more about TRISEL, please visit Doctor s Name: Nurse s Name: Phone Number: Fax Number: Emergency Phone Number: ther Information: For additional information about TRISEL, please see the Prescribing Information in the pocket. Please see Important Safety Information starting on page

9 injection Kit HIGHLIGHTS F PRESCRIBING INFRMATIN These highlights do not include all the information needed to use TRISEL safely and effectively. See full prescribing information for TRISEL. TRISEL Kit (temsirolimus) injection, for intravenous infusion only Initial U.S. approval: 2007 INDICATINS AND USAGE TRISEL is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma. (1) DSAGE AND ADMINISTRATIN The recommended dose of TRISEL is 25 mg infused over a minute period once a week. Treat until disease progression or unacceptable toxicity. (2.1) Antihistamine pre-treatment is recommended. (2.2) TRISEL (temsirolimus) injection vial contents must first be diluted with the enclosed diluent before diluting the resultant solution with 250 ml of 0.9% sodium chloride injection. (2.5) DSAGE FRMS AND STRENGTHS TRISEL injection, 25 mg/ml supplied with DILUENT for TRISEL. (3) CNTRAINDICATINS None. (4) WARNINGS AND PRECAUTINS To treat hypersensitivity reactions stop TRISEL and treat with an antihistamine. TRISEL may be restarted at physician discretion at a slower rate. (5.1) Hyperglycemia and hyperlipemia are likely and may require treatment. Monitor glucose and lipid profiles. (5.2, 5.5) Infections may result from immunosuppression. (5.3) Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue FULL PRESCRIBING INFRMATIN: CNTENTS* 1 INDICATINS AND USAGE 2 DSAGE AND ADMINISTRATIN 2.1 Advanced Renal Cell Carcinoma 2.2 Premedication 2.3 Dosage Interruption/Adjustment 2.4 Dose Modification Guidelines 2.5 Instructions for Preparation and Administration 3 DSAGE FRMS AND STRENGTHS 4 CNTRAINDICATINS 5 WARNINGS AND PRECAUTINS 5.1 Hypersensitivity Reactions 5.2 Hyperglycemia/Glucose Intolerance 5.3 Infections 5.4 Interstitial Lung Disease 5.5 Hyperlipemia 5.6 Bowel Perforation 5.7 Renal Failure 5.8 Wound Healing Complications 5.9 Intracerebral Hemorrhage 5.10 Co-administration with Inducers or Inhibitors of CYP3A Metabolism 5.11 Concomitant use of TRISEL with sunitinib 5.12 Vaccinations 5.13 Pregnancy 5.14 Monitoring Laboratory Tests TRISEL, and consider use of corticosteroids and/or antibiotics. (5.4) Bowel perforation may occur. Evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly. (5.6) Renal failure, sometimes fatal, has occurred. Monitor renal function at baseline and while on TRISEL. (5.7) Due to abnormal wound healing, use TRISEL with caution in the perioperative period. (5.8) Live vaccinations and close contact with those who received live vaccines should be avoided. (5.12) Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. (5.13) ADVERSE REACTINS The most common adverse reactions (incidence 30%) are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (incidence 30%) are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. (6) To report SUSPECTED ADVERSE REACTINS, contact Wyeth Pharmaceuticals Inc. at or FDA at FDA-1088 or DRUG INTERACTINS Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite of TRISEL. If alternatives cannot be used, dose modifications of TRISEL are recommended. (7.1, 7.2) See 17 for PATIENT CUNSELING INFRMATIN. Revised: 09/ ADVERSE REACTINS 6.1 Clinical Trials Experience 7 DRUG INTERACTINS 7.1 Agents Inducing CYP3A Metabolism 7.2 Agents Inhibiting CYP3A Metabolism 7.3 Interactions with Drugs Metabolized by CYP2D6 8 USE IN SPECIFIC PPULATINS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 VERDSAGE 11 DESCRIPTIN 12 CLINICAL PHARMACLGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NNCLINICAL TXICLGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HW SUPPLIED/STRAGE AND HANDLING 17 PATIENT CUNSELING INFRMATIN *Sections or subsections omitted from the full prescribing information are not listed. 1

10 TRISEL Kit (temsirolimus) injection FULL PRESCRIBING INFRMATIN 1 INDICATINS AND USAGE TRISEL is indicated for the treatment of advanced renal cell carcinoma. 2 DSAGE AND ADMINISTRATIN 2.1 Advanced Renal Cell Carcinoma The recommended dose of TRISEL for advanced renal cell carcinoma is 25 mg infused over a minute period once a week. Treatment should continue until disease progression or unacceptable toxicity occurs. 2.2 Premedication Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of TRISEL [see Hypersensitivity Reactions (5.1)]. 2.3 Dosage Interruption/Adjustment TRISEL should be held for absolute neutrophil count (ANC) < 1,000/mm 3, platelet count < 75,000/mm 3, or NCI CTCAE grade 3 or greater adverse reactions. nce toxicities have resolved to grade 2 or less, TRISEL may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week. 2.4 Dose Modification Guidelines Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a TRISEL dose reduction to 12.5 mg/week should be considered. This dose of TRISEL is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the TRISEL dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor. [see Drug Interactions (7.2)] Concomitant Strong CYP3A4 Inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a TRISEL dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of TRISEL is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer. [see Drug Interactions (7.1)] 2.5 Instructions for Preparation and Administration TRISEL must be stored under refrigeration at 2º-8ºC (36º-46ºF) and protected from light. During handling and preparation of admixtures, TRISEL should be protected from excessive room light and sunlight. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final TRISEL dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Dilution: In preparing the TRISEL administration solution, follow this two-step dilution process in an aseptic manner. Step 1: Inject 1.8 ml of DILUENT for TRISEL into the vial of TRISEL (temsirolimus) injection (25 mg/ml). The TRISEL (temsirolimus) vial contains an overfill of 0.2 ml (30 mg/ 1.2 ml). Due to the intentional overfill in the TRISEL injection vial, the drug concentration of the resulting solution will be 10 mg/ml. A total volume of 3 ml will be obtained including the overfill. Mix well by inversion of the vial. Allow sufficient time for air bubbles to subside. This 10 mg/ml drug solution/diluent mixture must be further diluted as described in Step 2 below. The solution is clear to slightly turbid, colorless to yellow, and free from visual particulates. The 10 mg/ml drug solution/diluent mixture is stable for up to 24 hours at controlled room temperature. Step 2: Withdraw the required amount of temsirolimus from the 10 mg/ml drug solution/diluent mixture prepared in Step 1. Inject rapidly into a 250 ml container (glass, polyolefin, or polyethylene) of 0.9% sodium chloride injection. Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming. Administration: The sodium chloride injection container should be composed of non-dehp containing materials, such as glass, polyolefin or polyethylene, and the administration set should consist of non-dehp tubing to avoid extraction of di-(2-ethylhexyl) phthalate (DEHP). TRISEL contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from PVC. An inline polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration. The final diluted solution of TRISEL is intravenously infused over a minute period once a week. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the drug. Administration of the final diluted infusion solution should be completed within six hours from the time that the drug solution/diluent mixture is added to the sodium chloride injection. Compatibilities and Incompatibilities Undiluted TRISEL injection should not be added directly to aqueous infusion solutions. Direct addition of TRISEL injection to aqueous solutions will result in precipitation of drug. Always combine TRISEL injection with DILUENT for TRISEL before adding to infusion solutions. It is recommended that TRISEL be administered in 0.9% sodium chloride injection after combining with diluent. The stability of TRISEL in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of TRISEL in sodium chloride injection has not been evaluated and should be avoided. Temsirolimus is degraded by both 2

11 TRISEL Kit (temsirolimus) injection acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution ph should be avoided. 3 DSAGE FRMS AND STRENGTHS TRISEL (temsirolimus) is supplied as a kit consisting of the following: TRISEL (temsirolimus) injection (25 mg/ml). The TRISEL vial includes an overfill of 0.2 ml. DILUENT for TRISEL. The DILUENT vial includes a deliverable volume of 1.8 ml. 4 CNTRAINDICATINS None. 5 WARNINGS AND PRECAUTINS 5.1 Hypersensitivity Reactions Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have been observed with TRISEL. TRISEL should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of TRISEL. An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TRISEL should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons. If a patient develops a hypersensitivity reaction during the TRISEL infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered [see Dosage and Administration (2.2)], and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TRISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes). 5.2 Hyperglycemia/Glucose Intolerance The use of TRISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TRISEL had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with TRISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination. 5.3 Infections The use of TRISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections [see Adverse Reactions (6.1)]. 5.4 Interstitial Lung Disease Cases of interstitial lung disease, some resulting in death, occurred in patients who received TRISEL. Some patients were asymptomatic with infiltrates detected on computed tomography scan or chest radiograph. thers presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TRISEL and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms. 5.5 Hyperlipemia The use of TRISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TRISEL had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TRISEL. 5.6 Bowel Perforation Cases of fatal bowel perforation occurred in patients who received TRISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools. 5.7 Renal Failure Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TRISEL. Some of these cases were not responsive to dialysis. 5.8 Wound Healing Complications Use of TRISEL has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of TRISEL in the perioperative period. 5.9 Intracerebral Hemorrhage Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TRISEL Co-administration with Inducers or Inhibitors of CYP3A Metabolism Agents Inducing CYP3A Metabolism: Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampacin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John s Wort may decrease TRISEL plasma concentrations unpredictably. Patients receiving TRISEL should not take St. John s Wort concomitantly. [see Dosage and Administration (2.4) and Drug Interactions (7.1)]. Agents Inhibiting CYP3A Metabolism: Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered. [see Dosage and Administration (2.4) and Drug Interactions (7.2)] Concomitant use of TRISEL with sunitinib The combination of TRISEL and sunitinib resulted in doselimiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of TRISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest). 3

12 TRISEL Kit (temsirolimus) injection 5.12 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TRISEL. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines Pregnancy Pregnancy Category D Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications. In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m 2 /day (approximately 0.04-fold the AUC in cancer patients at the human recommended dose). In rabbits, the intrauterine and embryofetal adverse effects were observed at the oral dose of 7.2 mg/m 2 /day (approximately 0.12-fold the AUC in cancer patients at the recommended human dose). Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TRISEL therapy has stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Men should be counseled regarding the effects of TRISEL on the fetus and sperm prior to starting treatment [see Nonclinical Toxicology (13.1)]. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of TRISEL Monitoring Laboratory Tests In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving TRISEL may need to be performed more or less frequently at the physician s discretion. 6 ADVERSE REACTINS The following serious adverse reactions have been associated with TRISEL in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5 )]. Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.2)] Interstitial Lung Disease [see Warnings and Precautions (5.4)] Hyperlipemia [see Warnings and Precautions (5.5)] Bowel Perforation [see Warnings and Precautions (5.6)] Renal Failure [see Warnings and Precautions (5.7)] The most common ( 30%) adverse reactions observed with TRISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common ( 30%) laboratory abnormalities observed with TRISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the Phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, TRISEL alone, and TRISEL and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received TRISEL 25 mg weekly, and 208 patients received a combination of TRISEL and IFN-α weekly [see Clinical Studies (14)]. Treatment with the combination of TRISEL 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone. Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TRISEL 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison. Table 1 Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TRISEL or IFN-α in the Randomized Trial TRISEL IFN-α 25 mg Adverse Reaction n=208 n=200 All Grades All Grades Grades* 3&4* Grades* 3&4* n (%) n (%) n (%) n (%) Any 208 (100) 139 (67) 199 (100) 155 (78) General disorders Asthenia 106 (51) 23 (11) 127 (64) 52 (26) Edema a 73 (35) 7 (3) 21 (11) 1 (1) Pain 59 (28) 10 (5) 31 (16) 4 (2) Pyrexia 50 (24) 1 (1) 99 (50) 7 (4) Weight Loss 39 (19) 3 (1) 50 (25) 4 (2) Headache 31 (15) 1 (1) 30 (15) 0 (0) Chest Pain 34 (16) 2 (1) 18 (9) 2 (1) Chills 17 (8) 1 (1) 59 (30) 3 (2) Gastrointestinal disorders Mucositis b 86 (41) 6 (3) 19 (10) 0 (0) Anorexia 66 (32) 6 (3) 87 (44) 8 (4) Nausea 77 (37) 5 (2) 82 (41) 9 (5) Diarrhea 56 (27) 3 (1) 40 (20) 4 (2) Abdominal Pain 44 (21) 9 (4) 34 (17) 3 (2) Constipation 42 (20) 0 (0) 36 (18) 1 (1) Vomiting 40 (19) 4 (2) 57 (29) 5 (3) Infections Infections c 42 (20) 6 (3) 19 (10) 4 (2) Urinary tract infection d 31 (15) 3 (1) 24 (12) 3 (2) Pharyngitis 25 (12) 0 (0) 3 (2) 0 (0) Rhinitis 20 (10) 0 (0) 4 (2) 0 (0) Musculoskeletal and connective tissue disorders Back Pain 41 (20) 6 (3) 28 (14) 7 (4) Arthralgia 37 (18) 2 (1) 29 (15) 2 (1) Myalgia 16 (8) 1 (1) 29 (15) 2 (1) 4

13 TRISEL Kit (temsirolimus) injection Table 1 Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TRISEL or IFN-α in the Randomized Trial TRISEL IFN-α 25 mg Adverse Reaction n=208 n=200 All Grades All Grades Grades* 3&4* Grades* 3&4* n (%) n (%) n (%) n (%) Any 208 (100) 139 (67) 199 (100) 155 (78) Respiratory, thoracic and mediastinal disorders Dyspnea 58 (28) 18 (9) 48 (24) 11 (6) Cough 53 (26) 2 (1) 29 (15) 0 (0) Epistaxis 25 (12) 0 (0) 7 (4) 0 (0) Skin and subcutaneous tissue disorders Rash e 97 (47) 10 (5) 14 (7) 0 (0) Pruritus 40 (19) 1 (1) 16 (8) 0 (0) Nail Disorder 28 (14) 0 (0) 1 (1) 0 (0) Dry Skin 22 (11) 1 (1) 14 (7) 0 (0) Acne 21 (10) 0 (0) 2 (1) 0 (0) Nervous system disorders Dysgeusia f 41 (20) 0 (0) 17 (9) 0 (0) Insomnia 24 (12) 1 (1) 30 (15) 0 (0) Depression 9 (4) 0 (0) 27 (14) 4 (2) *Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. a Includes edema, facial edema, and peripheral edema b Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis c Includes infections not otherwise specified (NS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection e Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NS), and vesiculobullous rash f Includes taste loss and taste perversion The following selected adverse reactions were reported less frequently (<10%). Gastrointestinal Disorders Fatal bowel perforation occurred in 1 patient (1%). Eye Disorders - Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%). Immune System - Allergic/Hypersensitivity reactions occurred in 18 patients (9%). Angioneurotic edema-type reactions have been observed in some patients who received TRISEL and ACE inhibitors concomitantly. Infections - Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 14 patients (7%). General Disorders and Administration Site Conditions - Impaired wound healing occurred in 3 patients (1%). Respiratory, Thoracic and Mediastinal Disorders Interstitial lung disease occurred in 5 patients (2%), including rare fatalities. Vascular - Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%). Table 2 Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TRISEL or IFN-α in the Randomized Trial TRISEL IFN-α 25 mg n=208 n=200 Laboratory Abnormality All Grades All Grades Grades* 3&4* Grades* 3&4* n (%) n (%) n (%) n (%) Any 208 (100) 162 (78) 195 (98) 144 (72) Hematology Hemoglobin Decreased 195 (94) 41 (20) 180 (90) 43 (22) Lymphocytes Decreased** 110 (53) 33 (16) 106 (53) 48 (24) Neutrophils Decreased** 39 (19) 10 (5) 58 (29) 19 (10) Platelets Decreased 84 (40) 3 (1) 51 (26) 0 (0) Leukocytes Decreased 67 (32) 1 (1) 93 (47) 11 (6) Chemistry Alkaline Phosphatase Increased 141 (68) 7 (3) 111 (56) 13 (7) AST Increased 79 (38) 5 (2) 103 (52) 14 (7) Creatinine Increased 119 (57) 7 (3) 97 (49) 2 (1) Glucose Increased 186 (89) 33 (16) 128 (64) 6 (3) Phosphorus Decreased 102 (49) 38 (18) 61 (31) 17 (9) Total Bilirubin Increased 16 (8) 2 (1) 25 (13) 4 (2) Total Cholesterol Increased 181 (87) 5 (2) 95 (48) 2 (1) Triglycerides Increased 173 (83) 92 (44) 144 (72) 69 (35) Potassium Decreased 43 (21) 11 (5) 15 (8) 0 (0) *NCI CTC version 3.0 **Grade 1 toxicity may be under-reported for lymphocytes and neutrophils 7 DRUG INTERACTINS 7.1 Agents Inducing CYP3A Metabolism Co-administration of TRISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to TRISEL treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered [see Dosage and Administration (2.4)]. 7.2 Agents Inhibiting CYP3A Metabolism Co-administration of TRISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2-fold compared to TRISEL alone. If alternative treatment cannot be administered, a dose adjustment should be considered. [see Dosage and Administration (2.4)]. 7.3 Interactions with Drugs Metabolized by CYP2D6 The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of TRISEL was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4. 8 USE IN SPECIFIC PPULATINS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.13)]. 8.3 Nursing Mothers 5

14 TRISEL Kit (temsirolimus) injection It is not known whether TRISEL is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of TRISEL) in animal studies, a decision should be made whether to discontinue nursing or discontinue TRISEL, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TRISEL in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of TRISEL did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 8.6 Renal Impairment No clinical studies were conducted with TRISEL in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [ 14 C]-labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of TRISEL is recommended in patients with renal impairment. TRISEL has not been studied in patients undergoing hemodialysis. 8.7 Hepatic Impairment Temsirolimus is cleared predominantly by the liver. No data are currently available regarding the influence of hepatic dysfunction on temsirolimus disposition. 10 VERDSAGE There is no specific treatment for TRISEL intravenous overdose. TRISEL has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m 2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of TRISEL greater than 25 mg. 11 DESCRIPTIN Temsirolimus, an inhibitor of mtr, is an antineoplastic agent. Temsirolimus is a white to off-white powder with a molecular formula of C56H87N16 and a molecular weight of It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of ph. The chemical name of temsirolimus is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R, 34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a- Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4- hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21- dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy- 3H- pyrido[2,1-c][1,4]oxaazacyclohentriacontine- 1,5,11,28,29(4H,6H,31H)-pentone 4 -[2,2- bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-hydroxy- 2-(hydroxymethyl)-2-methylpropanoate]. H3C CH3 H CH3 N H3C CH3 H3C CH3 H CH3 CH3 H3C H H TRISEL (temsirolimus) injection, 25 mg/ml, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. TRISEL (temsirolimus) injection requires two dilutions prior to intravenous infusion. TRISEL (temsirolimus) injection should be diluted only with the supplied DILUENT for TRISEL. DILUENT for TRISEL is a sterile, non-aqueous solution that is supplied with TRISEL injection, as a kit. TRISEL (temsirolimus) injection, 25 mg/ml: Active ingredient: temsirolimus (25 mg/ml) Inactive ingredients: dehydrated alcohol (39.5% w/v), dl-alphatocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v). DILUENT for TRISEL Inactive ingredients: polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v). After the TRISEL (temsirolimus) injection vial has been diluted with DILUENT for TRISEL, in accordance with the instructions in section 2.5, the solution contains 35.2% alcohol. TRISEL (temsirolimus) injection and DILUENT for TRISEL are filled in clear glass vials with butyl rubber stoppers. 12 CLINICAL PHARMACLGY 12.1 Mechanism of Action Temsirolimus is an inhibitor of mtr (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mtr that controls cell division. Inhibition of mtr activity resulted in a G1 growth arrest in treated tumor cells. When mtr was inhibited, its ability to phosphorylate p70s6k and S6 ribosomal protein, which are downstream of mtr in the PI3 kinase/akt pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mtr and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor Pharmacokinetics Absorption Following administration of a single 25 mg dose of TRISEL in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/ml (coefficient of variation, CV =14%), and mean AUC in blood was 1627 ng h/ml (CV=26%). Typically Cmax occurred at the end of infusion. ver the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus. Distribution Following a single 25 mg intravenous dose, mean steadystate volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements. Metabolism Cytochrome P450 3A4 is the major isozyme responsible for the formation of five temsirolimus metabolites. Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the CH3

15 TRISEL Kit (temsirolimus) injection metabolites account for less than 10% of radioactivity in the plasma. In human liver microsomes temsirolimus was an inhibitor of CYP2D6 and 3A4. However, there was no effect observed in vivo when temsirolimus was administered with desipramine (a CYP2D6 substrate), and no effect is anticipated with substrates of CYP3A4 metabolism. Elimination Elimination is primarily via the feces. After a single IV dose of [ 14 C]-temsirolimus approximately 82% of total radioactivity was eliminated within 14 days, with 4.6% and 78% of the administered radioactivity recovered in the urine and feces, respectively. Following a single 25 mg dose of TRISEL in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/h. Temsirolimus exhibits a biexponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively. Effects of Age and Gender In population pharmacokinetic-based data analyses, no relationship was apparent between drug exposure and patient age or gender. 13 NNCLINICAL TXICLGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with temsirolimus. However, sirolimus, the major metabolite of temsirolimus in humans, was carcinogenic in mice and rats. The following effects were reported in mice and/or rats in the carcinogenicity studies conducted with sirolimus: lymphoma, hepatocellular adenoma and carcinoma, and testicular adenoma. Temsirolimus was not genotoxic in a battery of in vitro (bacterial reverse mutation in Salmonella typhimurium and Escherichia coli, forward mutation in mouse lymphoma cells, and chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays. In male rats, the following fertility effects were observed: decreased number of pregnancies, decreased sperm concentration and motility, decreased reproductive organ weights, and testicular tubular degeneration. These effects were observed at oral temsirolimus doses 3 mg/m 2 /day (approximately 0.2-fold the human recommended intravenous dose). Fertility was absent at 30 mg/m 2 /day. In female rats, an increased incidence of pre- and postimplantation losses occurred at oral doses 4.2 mg/m 2 /day (approximately 0.3-fold the human recommended intravenous dose), resulting in decreased numbers of live fetuses. 14 CLINICAL STUDIES A phase 3, multi-center, three-arm, randomized, open-label study was conducted in previously untreated patients with advanced renal cell carcinoma (clear cell and non-clear cell histologies). The objectives were to compare verall Survival (S), Progression-Free Survival (PFS), bjective Response Rate (RR), and safety in patients receiving IFN-α to those receiving TRISEL or TRISEL plus IFN-α. Patients in this study had 3 or more of 6 pre-selected prognostic risk factors (less than one year from time of initial RCC diagnosis to randomization, Karnofsky performance status of 60 or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dl, lactate dehydrogenase > 1.5 times the upper limit of normal, more than one metastatic organ site). Patients were stratified for prior nephrectomy status within three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n=207), TRISEL alone (25 mg weekly; n=209), or the combination arm (n=210). The ITT population for this interim analysis included 626 patients. Demographics were comparable between the three treatment arms with regard to age, gender, and race. The mean age of all groups was 59 years (range 23-86). Sixtynine percent were male and 31% were female. The racial distribution for all groups was 91% White, 4% Black, 2% Asian, and 3% other. Sixty-seven percent of patients had a history of prior nephrectomy. The median duration of treatment in the TRISEL arm was 17 weeks (range weeks). The median duration of treatment on the IFN arm was 8 weeks (range weeks). There was a statistically significant improvement in S (time from randomization to death) in the TRISEL 25 mg arm compared to IFN-α. The combination of TRISEL 15 mg and IFN-α did not result in a significant increase in overall survival when compared with IFN-α alone. Figure 1 is a Kaplan-Meier plot of S in this study. The evaluations of PFS (time from randomization to disease progression or death) and RR, were based on blinded independent radiologic assessment of tumor response. Efficacy results are summarized in Table 3. Table 3: Summary of Efficacy Results of TRISEL vs. IFN-α TRISEL IFN-α P-value a Hazard Ratio Parameter (95% CI) b n = 209 n = 207 Median verall Survival Months (95% CI) Median Progression-Free Survival Months (95% CI) verall Response Rate % (95% CI) * 0.73 (8.6, 12.7) (6.1, 8.8) (0.58, 0.92) ** 0.66 (3.9, 7.0) (2.2, 3.8) (0.53, 0.81) ** c NA (4.8, 12.4) (1.9, 7.8) CI = confidence interval; NA = not applicable * A comparison is considered statistically significant if the p-value is < ( Brien-Fleming boundary at 446 deaths). ** Not adjusted for multiple comparisons. a Based on log-rank test stratified by prior nephrectomy and region. b Based on Cox proportional hazard model stratified by prior nephrectomy and region. c Based on Cochran-Mantel-Haenszel test stratified by prior nephrectomy and region. Survival Distribution Function Figure 1: Kaplan Meier Curves for verall Survival TRISEL vs. IFN Months to Death from Randomization Interferon TRISEL 25 mg 7

16 TRISEL Kit (temsirolimus) injection 15 REFERENCES 1. NISH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for ccupational Safety and Health, DHHS (NISH) Publication No SHA Technical Manual, TED A, Section VI: Chapter 2. Controlling ccupational Exposure to Hazardous Drugs. SHA, NIH [2002] recommendations for the safe handling of cytotoxic drugs. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. 5. Polovich, M., White, J. M., & Kelleher, L.. (eds.) Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: ncology Nursing Society. 16 HW SUPPLIED/STRAGE AND HANDLING NDC TRISEL (temsirolimus) injection, 25 mg/ml. NDC DILUENT for TRISEL, 1.8 ml (deliverable volume) per vial. These two vials are supplied as a kit in a single carton, and must be stored at 2º-8ºC (36º-46ºF). Protect from light. U.S. Patent No. 5,362, PATIENT CUNSELING INFRMATIN Allergic (Hypersensitivity) Reactions Patients should be informed of the possibility of serious allergic reactions, including anaphylaxis, despite premedication with antihistamines, and to immediately report any facial swelling or difficulty breathing [see Warnings and Precautions (5.1)]. Increased Blood Glucose Levels Patients are likely to experience increased blood glucose levels while taking TRISEL. This may result in the need for initiation of, or increase in the dose of, insulin and/or hypoglycemic agents. Patients should be directed to report any excessive thirst or frequency of urination to their physician [see Warnings and Precautions (5.2)]. Infections Patients should be informed that they may be more susceptible to infections while being treated with TRISEL [see Warnings and Precautions (5.3)]. Interstitial Lung Disease Patients should be warned of the possibility of developing interstitial lung disease, a chronic inflammation of the lungs, which may rarely result in death [see Warnings and Precautions (5.4)]. Patients should be directed to report promptly any new or worsening respiratory symptoms to their physician. Increased Blood Triglycerides and/or Cholesterol Patients are likely to experience elevated triglycerides and/or cholesterol during TRISEL treatment. This may require initiation of, or increase in the dose of, lipidlowering agents [see Warnings and Precautions (5.5)]. Bowel Perforation Patients should be warned of the possibility of bowel perforation. Patients should be directed to report promptly any new or worsening abdominal pain or blood in their stools [see Warnings and Precautions (5.6)]. Renal Failure Patients should be informed of the risk of renal failure [see Warnings and Precautions (5.7)]. Wound Healing Complications Patients should be advised of the possibility of abnormal wound healing if they have surgery within a few weeks of initiating therapy or during therapy [see Warnings and Precautions (5.8)]. Intracerebral Bleeding Patients with CNS tumors and/or receiving anticoagulants should be informed of the increased risk of developing intracerebral bleeding (including fatal outcomes) while on TRISEL [see Warnings and Precautions (5.9)]. Medications that can interfere with TRISEL Some medicines can interfere with the breakdown or metabolism of TRISEL. In particular, patients should be directed to inform their physician if they are taking any of the following: Protease inhibitors, anti-epileptic medicines including carbamazepine, phenytoin, and barbiturates, St. John s Wort, rifampicin, rifabutin, nefazodone or selective serotonin re-uptake inhibitors used to treat depression, antibiotics or antifungal medicines used to treat infections [see Warnings and Precautions (5.10)]. Vaccinations Patients should be advised that vaccinations may be less effective while being treated with TRISEL. In addition, the use of live vaccines, and close contact with those who have received live vaccines, while on TRISEL should be avoided. [see Warnings and Precautions (5.12)]. Pregnancy TRISEL can cause fetal harm. Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TRISEL therapy has stopped. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of TRISEL. [see Warnings and Precautions (5.13)]. Wyeth Pharmaceuticals Inc. Philadelphia, PA Manufactured for: Wyeth Pharmaceuticals Inc. Philadelphia, PA TRISEL (temsirolimus) injection is manufactured by: Pierre Fabre Medicament Production, Aquitaine Pharm International, Avenue du Bearn, F64320 Idron, France DILUENT for TRISEL is manufactured by: Ben Venue Laboratories, Inc., Bedford, hio W10524C004 ET01 Rev 09/08 8